Diastereomer salt of optically active quinolinemevalonic acid

ABSTRACT

A diastereomer salt of optically active quinolinemevalonic acid of the formula ((-)I.(+)II): ##STR1##

The present invention relates to an important intermediate for thepreparation of optically active quinolinemevalonic acid derivativesuseful for the prevention or treatment of hyperlipemia,arteriosclerosis, etc. and a method for optically resolution thereof.

A quinolinemevalonic acid compound of the formula (V) and aquinolinemevalonolactone compound of the formula (VI): ##STR2## whereinR¹ is a hydrogen atom, a C₁₋₄ lower alkyl group such as a methyl group,an ethyl group, a n-propyl group, an i-propyl group, a t-butyl group, an-butyl group, an i-butyl group, a s-butyl group, or Na, K, 1/2Ca orHNR² R³ R⁴ wherein each of R², R³ and R⁴ is hydrogen, a C₁₋₃ lower alkylgroup or a 2-hydroxyethyl group, or when R² hydrogen or methyl, R³ andR⁴ together form --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₂ --O--(CH₂)₂ --or--(CH₂)₂ --NH--(CH₂)₂ --, are racemic mixtures or compounds having fouroptical isomers, as disclosed in Japanese and European Unexamined PatentPublication Nos. 279866/1989 and 304063, and they are strong inhibitorsagainst HMG-CoA reductase which is a rate limiting enzyme for thebiosynthesis of cholesterol and thus expected to be useful as drugs forthe prevention and treatment of hyperlipemia, arteriosclerosis, etc.

Further, quinolinecarboxylic acid derivatives as HMG-CoA reductaseinhibitors are disclosed, for example, in the following literatures:German Patent DE-3905908, U.S. Pat. No. 4,761,419, U.S. Pat. No.4,923,861 and European Patent Publication EP 356788A.

As disclosed in Japanese and European Unexamined Patent Publication Nos.279866/1989 and 304063, the compounds of the formulas (V) and (VI) canbe prepared as follows: ##STR3## In the above formulas, each of R⁵, R⁶and R⁷ is a C₁₋₄ lower alkyl group such as a methyl group, an ethylgroup, a n-propyl group, an i-propyl group, a t-butyl group, a n-butylgroup, an i-butyl group or a s-butyl group.

Step A is a reduction reaction of an ester (VII) to a primary alcohol(VIII), and the reaction can be conducted in a solvent such astetrahydrofuran or toluene at a temperature of from -20° C. to 20° C.,preferably from -10° C. to 10° C., using various metal hydrides,preferably diisobutylaluminum hydride.

Step B is an oxidation reaction of the primary alcohol (VIII) to analdehyde (IX), and the reaction can be conducted using various oxidizingagents. Preferred is a method wherein oxidation is conducted at atemperature of from 0° C. to 25° C. using pyridinium chlorochromate inmethylene chloride, a method wherein oxidation is conducted using oxalylchloride, dimethyl sulfoxide and a tertiary amine (such astriethylamine) (Swern oxidation), a method wherein oxidation isconducted using phosphorus pentoxide, dimethyl sulfoxide and a tertiaryamine (such as triethylamine) or a method wherein oxidation is conductedusing sulfur trioxidepyridine complex.

Step C is a reaction for the preparation of an α,β-unsaturatedcarboxylic acid ester (X), whereby a transform α,β-unsaturatedcarboxylic acid ester (X) can be obtained by so-called Horner-Wittigreaction using an alkoxycarbonylmethyl phosphonate. As the base, sodiumhydride, potassium-t-butoxide or the like is employed, and the reactionis conducted in dry tetrahydrofuran at a temperature of from -30° C. to0° C., preferably from -20° C. to -15° C.

Step D is a reduction reaction of the α,β-unsaturated carboxylic acidester (X) to an allyl alcohol (XI), and the reaction can be conducted ina solvent such as dry tetrahydrofuran or toluene at a temperature offrom -10° C. to 10° C., preferably from -10° C. to 0° C., using variousmetal hydrides, preferably diisobutylaluminum hydride.

Step E is an oxidation reaction of the allyl alcohol (XI) to an enal(XII), and the reaction is conducted using various oxidizing agents.Preferred is a method wherein oxidation is conducted in a solvent suchas tetrahydrofuran, acetone, ethyl ether or ethyl acetate at atemperature of from 0° C. to 100° C., preferably from 15° C. to 50° C.,using activated manganese dioxide, a method wherein oxidation isconducted using a sulfur trioxidepyridine complex, a method whereinoxidation is conducted using phosphorus pentoxide, dimethylsulfoxide anda tertiary amine (such as triethyl amine), or more preferably a methodwherein oxidation is conducted using oxalyl chloride, dimethyl sulfoxideand a tertiary amine (such as triethylamine) (Swern oxidation).

Step F is a condensation reaction of the enal (XII) and a double anionof an acetoacetate, and the reaction is preferably conducted intetrahydrofuran at a temperature of from -80° C. to 20° C., preferablyfrom -30° C. to 0° C., using sodium hydride as the base and n-butyllithium.

Step G is a reduction reaction of the carbonyl group of the compound(XIII). There is a method wherein the reduction is conducted in ethanolat a temperature of from -10° C. to 5° C. using a metal hydride,preferably sodium borohydride, a method wherein the reduction isconducted in dry ether or dry tetrahydrofuran at a temperature of from-100° C. to 25° C., preferably from -80° C. to -50° C. using zincborohydride, and more preferably a method wherein the reduction isconducted in dry tetrahydrofuran-methanol at a temperature of from -80°C. to -60° C. using sodium borohydride and triethylborane ordiethylmethoxyborane. (The compound (XIV) corresponds to the compound(V) wherein R¹ is a C₁₋₄ lower alkyl group.)

Step H is a step for hydroryzing the ester (XIV), which can be conductedin a solvent mixture of methanol or ethanol with water at a temperatureof from 10° C. to 25° C. using an equimolar amount of a base, preferablypotassium hydroxide or sodium hydroxide. (The compound (XV) correspondsto the compound (V) wherein R¹ is a hydrogen atom.)

Step J is a step for forming mevalonolactone by a dehydration reactionof the free hydroxy acid (XV), and the reaction can be conducted using asuitable acid catalyst, preferably trifluoroacetic acid. Otherwise, thereaction can be conducted by removing the resulting water whilerefluxing in benzene or toluene under heating, or by adding a suitablewater-removing agent such as molecular sieves. Further, the reaction canbe conducted at a temperature of from 10° C. to 35° C., preferably from20° C. to 25° C., using a lactone-modifying agent in dry methylenechloride, such as a carbodiimide, preferably a water-solublecarbodiimide such asN-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimidep-toluenesulfonate.

With respect to drugs, there are many cases in which the pharmacologicalactivities and safety differ among optical isomers. In order to developan excellent drug, it is desired to separate them by optical resolution.

However, there has been no method for optical resolution known to beindustrially useful for the separation of the racemic modification ofthe quinolinemevalonic acid ((±)I).

The present inventors have discovered that the racemic modification ofquinolinemevalonic acid ((±)I) forms a salt with D(+)phenethylamine((+)II) as an optically active amine, whereby theoptically active

lonic acid ((-)I) can be separated by optical resolution. The presentinvention has been accomplished on the basis of this discovery.

Thus, the present invention provides a diastereomer salt of opticallyactive quinolinemevalonic acid of the

formula ((-)I.(+)II): ##STR4##

The present invention provides also a method for optical resolution ofquinolinemevalonic acid ((+)I), which comprises reacting thequinolinemevalonic acid of the formula ((±)I) with D(+) phenethylamineof the formula ((+)II), and separating the resulting diastereomer saltof optically active quinolinemevalonic acid of the formula ((-)I.(+)II):##STR5##

Further, the present invention provides a process for producingoptically active quinolinemevalonic acid of the formula ((-)I), whichcomprises treating the diastereomer salt of optically activequinolinemevalonic acid of the formula ((-)I.(+)II), with an acid:##STR6##

Still further, the present invention provides a process for producingoptically active quinolinemevalonolactone of the formula (III), whichcomprises dehydrating the optically active quinolinemevalonic acid ofthe formula ((-)I): ##STR7##

The present invention further provides a process for producing opticallyactive quinolinemevalonic acid salt of the formula (IV), which comprisesreacting the optically active quinolinemevalonic acid of the formula((-)I), with a base: ##STR8## wherein R⁸ is Na, K, 1/2Ca or HNR² R³ R⁴wherein each of R², R³, R⁴ is hydrogen, a C₁₋₃ lower alkyl group or a2-hydroxyethyl group, or when R² is hydrogen or a methyl group, R³ andR⁴ together form --(CH₂)₄ --, --(CH₂)5--, --(CH₂)₂ --O--(CH₂)₂ -- or--(CH₂)₂ --NH--(CH₂)₂ --.

Furthermore, the present invention provides a process for producingoptically active quinolinemevalonic acid salt of the formula (IV), whichcomprises reacting the diastereomer salt of optically activequinolinemevalonic acid of the formula ((-)I.(+)II), with a base.

Now, the present invention will be described in detail with reference tothe preferred embodiments. ##STR9##

In the above formulas, R⁸ is Na, K, 1/2Ca or HNR² R³ R⁴ wherein each ofR², R³ and R⁴ is hydrogen, a C₁₋₃ lower alkyl group or a 2-hydroxyethylgroup, or when R² is hydrogen or methyl, R³ and R⁴ together form--(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₂ --O--(CH₂)₂ -- or --(CH₂)₂--NH--(CH₂)₂ --, and R⁹ is a C₁₋₄ lower alkyl group.

Step K is a step for hydroryzing a racemic ester (XVI), and thehydrolysis can be conducted in a solvent mixture of methanol or ethanolwith water at a temperature of from 0° C. to 25° C. using an equimolaramount of a base, preferably potassium hydroxide or sodium hydroxide,followed by neutralization using an aqueous acid solution, preferablyhydrochloric acid, to obtain a free quinoline mevalonic acid ((±)I).

Step L is a step for reacting D(+) phenethylamine (+)II) as an opticalresolution agent to the quinolinemevalonic acid ((±)I) for precipitationto obtain the diastereomer salt of optically active quinolinemevalonicacid ((-)I.(+)II) as crystals. Likewise, if L(-)phenethylamine((-)II) isused as an optical resolution agent, it is possible to obtain adiastereomer salt of optically active quinoline mevalonic acid((+)I.(-)II). Thus, by selecting the optical resolution agent, a desiredoptical isomer of the quinolinemevalonic acid ((±)I) can be obtained. Asthe solvent, a ketone-type solvent such as diethyl ketone or methylisobutyl ketone, or a solvent such as toluene or xylene may be usedalone, or a solvent mixture of such a solvent with an alcohol solventsuch as methanol or ethanol, or a solvent such as dimethylformamide ordimethyl sulfoxide, may preferably be used. The reaction temperature isusually from 0° C. to 100° C., and the precipitation is conductedusually at a temperature of from -20° C. to 100° C., preferably from-10° C. to 80° C.

In step M, the optically active quinolinemevalonic acid ((-)I) canreadily be obtained by treating the diastereomer salt of opticallyactive quinolinemevalonic acid ((-)I.(+)II) with various aqueous acidsolutions. As the acid, formic acid, trifluoroacetic acid orhydrochloric acid is preferred. Particularly preferred is hydrochloricacid.

Step N is a step for forming an optically activequinolinemevalonolactone (III) by a dehydration reaction of theoptically active quinolinemevalonic acid ((-)I), and the dehydrationreaction can be conducted using an acid catalyst, preferablytrifluoroacetic acid. Otherwise, the reaction can be conducted byremoving the resulting water while refluxing in benzene or toluene underheating, or by adding a water-removal agent such as molecular sieves.Further, the dehydration can be conducted at a temperature of from 10°C. to 35° C., preferably from 20° C. to 25° C., using alactone-modification agent in dry methylene chloride, such as acarbodiimide, preferably a water-soluble carbodiimide such asN-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimidep-toluenesulfonate.

Step O is a step of reacting the optically active quinolinemevalonicacid ((-)I) with a base to obtain an optically active quinolinemevalonicacid salt (IV). The base used here may be piperazine, morpholine,diethanolamine, triethanolamine, NaOH, KOH, Ca(OH)₂ or CaO.

In step P, the optically active quinolinemevalonic acid salt (IV) can beobtained from the diastereomer salt of optically activequinolinemevalonic acid ((-)I.(+)II) without isolating the opticallyactive quinolinemevalonic acid ((-)I). Namely, by adding an aqueoussolution of alkali metal hydroxide (such as sodium hydroxide orpotassium hydroxide) to the diastereomer salt of optically activequinolinemevalonic acid ((-)I.(+)II), it is possible to directly obtainan alkali metal salt (such as a quinolinemevalonic acid salt (IV)wherein R⁸ is Na or K). Further, by adding an aqueous solution of analkaline earth metal chloride (such as CaCl₂) to such an aqueous alkalimetal salt solution, it is possible to obtain an alkaline earth metalsalt (such as a quinolinemevalonic acid salt (IV) wherein R⁸ is 1/2Ca).

Now, the present invention will be described in detail with reference toExamples, but it should be understood that the present invention is byno means restricted by such specific Examples.

REFERENCE EXAMPLE 1(±)-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl]hept-6-ene acid compound ((±)I)

60 g of(±)-(E)-ethyl-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl]hept-6-enoate(a compound (XVI) wherein R9 is Et) was suspended in 100 ml of ethanol,and 200 ml of a 1N sodium hydroxide aqueous solution was added thereto.As the reaction proceeded, the suspension became a uniform solution.After completion of the hydrolysis, 200 ml of 1N hydrochloric acid wasadded thereto. This reaction solution was extracted with 500 ml ofdichloromethane to obtain the desired compound ((±)I).

H-NMR(CDCl₃), δppm 1.0-1.1 (m, 2H), 1.3-1.4 (m, 3H), 1.5-1.6 (m, 1H),2.3-2.4 (m, 1H), 2.51 (d, 2H, J =6.1), 2.8-3.5 (b, 3H), 4.1-4.2 (m, 1H),4.4-4.5 (m, 1H), 5.59 (dd, 1H, J=6.1, J=16.1), 6.63 (d, 1H, J=6.1),7.1-7.4 (m, 6H), 7.5-7.7 (m, 1H), 7.9-8.0 (m, 1H).

REFERENCE EXAMPLE 2 Resolution of a Diastereomer Salt Using a ChiralOrganic Amine

To the dichloromethane solution of the compound ((±)I) obtained inReference Example 1, 1 equivalent of a chiral organic amine asidentified in Table 1 was added, and then the solvent was distilled offto obtain a residue containing the corresponding diastereomer salt.Except for the case where the residue was oil, the residue was dissolvedunder heating in ten times by weight of methyl isobutylketone-dimethylformamide (20:1, v/v), followed by cooling to atemperature of from 10 to 25° C. for crystallization. For the opticalyield, the obtained diastereomer salt was treated with an acid and thenconverted to lactone, and the optical yield was measured by a highperformance liquid chromatography using an optical resolution column(chiraSpher, tradename, manufactured by E. Merck Company).

    ______________________________________                                        Resolution agent   Chemical Optical                                           (chiral organic amine)                                                                           yield (%)                                                                              yield (% ee)                                      ______________________________________                                        D(+)phenethylamine 44       73                                                R(+)α-(p-tolyl)ethylamine                                                                  .sup.  30.sup.1)                                                                       60                                                R(-)2-amino-1-butanol                                                                            80        0                                                D(-)α-phenylglycinol                                                                       .sup.  --.sup.2)                                                                       --                                                (-)N-benzyl-α-phenylethylamine                                                             .sup.  --.sup.2)                                                                       --                                                (-)p-bromo-α-phenylethylamine                                                              .sup.  --.sup.2)                                                                       --                                                ______________________________________                                         .sup.1) A gel substance precipitated.                                         .sup.2) The diastereomer salt was an oily substance.                     

EXAMPLE 1 (E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-clopropylquinolin-3'-yl]hept-6-ene acid.D(+) phenethylamine saltcompound ((-)I.(+)II)

To the dichloromethane solution of the compound ((±)I) obtained inReference Example 1, 16.2 g of D(+) phenethylamine ((+)II) was added,and the mixture was stirred. Then, dichloromethane was distilled off toobtain a residue. The residue was repeatedly crystallized from methylisobutyl ketone and methyl isobutyl ketone-ethanol (10:1, v/v) to obtain19.8 g of

the desired compound ((-)I.(+)II) as white crystals. (Melting point:144°-147° C., optical purity: 97%ee.)

EXAMPLE 2 (E)-6(S)-[4'-(4"-flurophenyl)-2'-cyclopropylquinolin-3'-ylethenyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one compound(III)

To 14.08 g of(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl]hept-6-eneacid.D(+) phenethylamine salt compound ((-)I.(+)II) obtained in Example1, 25.9 ml of 1N hydrochrolic acid and 235 ml of water were added, andthe compound was dissolved. To this solution, 250 ml of ethyl acetatewas added to extract the compound ((-)I). The ethyl acetate solution waswashed with a saturated sodium chloride aqueous solution, and thesolvent was distilled off under reduced pressure. To the residue, 250 mlof dry toluene was added and refluxed under heating for 3 hours by meansof a Dean Stark apparatus. The solvent was distilled off under reducedpressure, and the residual solid thereby obtained was recrystallizedfrom toluene-heptane to obtain 6.4 g of the desired compound (III).(Melting point: 136°-139° C.).

EXAMPLE 3 (E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl]hept-6 -ene acid.1/2 calcium salt

To 12.0 g of(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'-yl]hept-6-ene acid.D(+) phenethylamine salt compound ((-)I.(+)II) obtainedin Example 1, 24.3 ml of a 1N sodium hydroxide aqueous solution and 200ml of water were added and stirred to dissolve the compound. To thissolution, an aqueous calcium chloride solution obtained by dissolving1.47 g of dry calcium chloride to 200 ml of water, was dropwise added.This reaction solution was stirred overnight, and the resulting whiteprecipitate was collected by filtration to obtain 9.0 g of whitecrystals (melting point: 190°-192° C. (decomposed)).

We claim:
 1. A diastereomer salt of optically active quinolinemevalonicacid of the formula ((-)I.(+)II): ##STR10##